CA2696404A1 - Therapeutic compounds - Google Patents

Therapeutic compounds Download PDF

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CA2696404A1
CA2696404A1 CA2696404A CA2696404A CA2696404A1 CA 2696404 A1 CA2696404 A1 CA 2696404A1 CA 2696404 A CA2696404 A CA 2696404A CA 2696404 A CA2696404 A CA 2696404A CA 2696404 A1 CA2696404 A1 CA 2696404A1
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methyl
alkyl
atoms
compound
dihydro
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Ken Chow
Wenkui K. Fang
Evelyn G. Corpuz
Dario G. Gomez
Santosh C. Sinha
Smita S. Bhat
Todd M. Heidelbaugh
Daniel W. Gil
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Allergan Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/28—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms

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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Disclosed herein is a compound having a structure (I), compositions, methods, and medicaments related thereto are also disclosed.

Description

THERAPEUTIC COMPOUNDS

By Inventors Ken Chow, Wenkui K. Fang, Evelyn G. Corpuz, Dario G. Gomez, Santosh C. Sinha, Smita S. Bhat, Todd M. Heidelbaugh, and Daniel W. Gil CROSS-REFERENCE
[1] This application claims the benefit of U.S. Provisional Application serial number 60/955,964, filed August 15, 2007, which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION
[2] There is a continuing need for alpha adrenergic compounds for treating pain, glaucoma and other conditions.
DESCRIPTION OF THE INVENTION
[3] Disclosed herein is a compound having a structure Rc Rb Rd ~

I HN
Ra \

\ ~N X
I
Re wherein X is 0, S, or NH;
Ra, Rb, R , and Ra are stable moieties independently consisting of: from 0 to 4 carbon atoms, from 0 to 10 hydrogen atoms, from 0 to 2 oxygen atoms, from 0 to 1 sulfur atoms, from 0 to 1 nitrogen atoms, from 0 to 3 fluorine atoms, from 0 to 1 chlorine atoms, and from 0 to 1 bromine atoms; and Re is H or Ci_4 alkyl.

[4] These compounds are useful for the treatment of pain, glaucoma, and the reduction of intraocular pressure. The compound is incorporated into a dosage form or a medicament and administered to the mammal in need thereof. For example, a liquid composition may be administered as an eye drop for the treatment of glaucoma or lowering intraocular pressure. A solid dosage form may also be administered orally for any of these conditions. Other types of dosage forms and medicaments are well known in the art, and may also be used here.
[5] For the purposes of this disclosure, "treat," "treating," or "treatment"
refer to the use of a compound, composition, therapeutically active agent, or drug in the diagnosis, cure, mitigation, treatment, prevention of disease or other undesirable condition.
[6] Unless otherwise indicated, reference to a compound should be construed broadly to include pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, and non-covalent complexes of a chemical entity of the depicted structure or chemical name.
[7] A pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt. A salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
[8] A prodrug is a compound which is converted to a therapeutically active compound after administration. While not intending to limit the scope of the invention, conversion may occur by hydrolysis of an ester group or some other biologically labile group. Prodrug preparation is well known in the art. For example, "Prodrugs and Drug Delivery Systems," which is a chapter in Richard B.
Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.
[9] Tautomers are isomers that are in rapid equilibrium with one another. For example, tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion. Examples of tautomers are depicted below.

Rc Rc Rb Rd Rb Rd ~ /

HN N
Ra \ Ra \
\~N~ X \~N )---X
I H
Re Re Rc Rc Rb Rd Rb Rd HN

Ra Ra )--,N N
N H H H

Re Rc Re Rb Rd HN
Ra H
N N
Re [10] Unless stereochemistry is explicitly depicted, a structure is intended to include every possible stereoisomer, both pure or in any possible mixture.
[11] Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein. For example, alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.
[12] Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.
[13] X is 0, S, or NH. Thus, compounds of any of the structures depicted below are contemplated.

R Rc Ro Rb Rd Rb Rd Rb Rd Ra HN--' Ra HN Ra HN
~ / ~ /~
~
H N~0 N~ S
JN
Re Re Re [14] The part of the compound:

HN
, 't") X

attaches to one of the non-aromatic carbons of the ring system. In other words, the compounds having the structures depicted below are contemplated.

Rc Rc Rb tRdR HN Rb Rd Ra N Ra HN
e te )__'X
R RN [15] Ra, Rb, R , and Rd are stable moieties independently consisting of:
from 0 to 4 carbon atoms, from 0 to 10 hydrogen atoms, from 0 to 2 oxygen atoms, from 0 to sulfur atoms, from 0 to 1 nitrogen atoms, from 0 to 3 fluorine atoms, from 0 to 1 chlorine atoms, and from 0 to 1 bromine atoms.
[16] Subject to the constraints described herein (e.g. limits on the number of atoms), examples of Ra, Rb, R , and Rd include, but are not limited to:
[17] Hydrocarbyl, meaning a moiety consisting of carbon and hydrogen only, including, but not limited to:
a. alkyl, meaning hydrocarbyl having no double or triple bonds, including, but not limited to:

= linear alkyl, e.g. methyl, ethyl, n-propyl, n-butyl, etc., = branched alkyl, e.g. iso-propyl, t-butyl and other branched butyl isomers, etc., = cycloalkyl, e.g. cyclopropyl, cyclobutyl, etc., = combinations of linear, branched, and/or cycloalkyl;
b. alkenyl, e.g. hydrocarbyl having 1 or more double bonds, including linear, branched, or cycloalkenyl c. alkynyl, e.g. hydrocarbyl having 1 or more triple bonds, including linear, branched, or cycloalkynyl;
d. combinations of alkyl, alkenyl, and/or akynyl [18] alkyl-CN, such as -CH2-CN, -(CH2)2-CN; -(CH2)3-CN, and the like;
[19] hydroxyalkyl, i.e. alkyl-OH, such as hydroxymethyl, hydroxyethyl, and the like;
[20] ether substituents, including -0-alkyl, alkyl-O-alkyl, and the like;
[21] thioether substituents, including -S-alkyl, alkyl-S-alkyl, and the like;
[22] amine substituents, including -NH2, -NH-alkyl,-N-alkylialkyh (i.e., alkyli and alkyh are the same or different, and both are attached to N), alkyl-NH2, alkyl-NH-alkyl, alkyl-N-alkylialkyh, and the like;
[23] aminoalkyl, meaning alkyl-amine, such as aminomethyl (-CH2-amine), aminoethyl, and the like;
[24] ester substituents, including -C02-alkyl, -COz_phenyl, etc.;

[25] other carbonyl substituents, including aldehydes; ketones, such as acyl (i.e.

-%?1hydro arbyi) and the like; in particular, acetyl, propionyl, and benzoyl substituents are contemplated;
[26] fluorocarbons or hydroflourocarbons such as -CF3, _CH2CF3, etc.; and [27] -CN;
[28] combinations of the above are also possible, subject to the constraints defined;
[29] Alternatively, a substituent may be -F, -Cl, -Br, or -I.
[30] In particular, alkyl having from 1 to 4 carbon atoms is contemplated;
[31] Ra, Rb, R , and Rd are stable, i.e. they are stable enough to be stored in a bottle at room temperature under a normal atmosphere for at least 12 hours, or stable enough to be useful for any purpose disclosed herein.
[32] If Ra, Rb, R , or Rd is a salt, for example of a carboxylic acid or an amine, the counter-ion of said salt, i.e. the ion that is not covalently bonded to the remainder of the molecule is not counted for the purposes of the number of atoms in the moiety.
Thus, for example, the salt -COz-Na+ consists of 1 carbon and 2 oxygen atoms, i.e.
sodium is not counted. In another example, the salt NH(Me)2+C1- consists of 2 carbon atoms, 1 nitrogen atom, and 7 hydrogen atoms, i.e. chlorine is not counted.
[33] In another embodiment, Ra, Rb, R , and Ra are independently -H, alkyl having from 1 to 4 carbon atoms, -F, -Cl, -Br, -CHzOH, an amine having from 0 to 4 carbon atoms, -CH2CN, -CF3, or acyl having from 1 to 4 carbon atoms.
[34] In another embodiment, Ra, Rb, R , and Ra are independently -H, -F, -Cl, -Br, -CH3, -NHCH3, or -CF3.
[35] Re is H or Ci_4 alkyl, i.e. methyl, ethyl, n-propyl, iso-propyl, and the butyl isomers. Re attaches to one of the non-aromatic carbons of the ring system.
Thus, compounds having any of the structures depicted below are contemplated.

R

) X N X
R
e Re [36] In another embodiment X is O.
[37] In another embodiment X is S.
[38] In another embodiment X is NH.
[39] In another embodiment Ra, Rb, R , and Ra are independently selected from H, methyl, ethyl, C3 alkyl, and C4 alkyl, F, Cl, Br, -CH20H, -CH2NH2, -CHNH(Ci_4 alkyl), -CN(Ci_4 alkyl)2, -CH2CN, and CF3.
[40] In another embodiment Ra, Rb, R , and Ra are independently selected from H, methyl, ethyl, F, Cl, Br, -CH2CN, and CF3.
[41] In another embodiment Re is H.
[42] In another embodiment Re is methyl.
[43] In another embodiment, the compound has a structure Rc Rb Rd HN
Ra N X
Re [44] In another embodiment, the compound has a structure R

Rb Rd Ra HN
le R N X

[45] Another embodiment is method of reducing intraocular pressure comprising administering a compound disclosed herein to a mammal in need thereof.
[46] Another embodiment is method of treating pain comprising administering a compound disclosed herein to a mammal in need thereof.
[47] Other useful compounds include:
[(1 R)-(4,5 -Dihydro-1 H-imidazol-2-yl)-(4-methyl-indan-l-yl)] -amine;
[(1 S)-(4,5-Dihydro-lH-imidazol-2-yl)-(4-methyl-indan-l-yl)]-amine;
(4,5-Dihydro-lH-imidazol-2-yl)-(6-methyl-indan-l-yl)-amine;
(4-Bromo-indan-1-yl)-(4,5-dihydro-lH-imidazol-2-yl)-amine;
[(1S)-(4,5-Dihydro-lH-imidazol-2-yl)-indan-l-yl] amine;

(4, 5 -Dihydro-1 H-imidazol-2 -yl)-indan-1-yl-amine;
(4,5-Dihydro-lH-imidazol-2-yl)-indan-2-yl-amine;
(4,5-Dihydro-oxazol-2-yl)-(4-methyl-indan-l-yl)-amine;
(4,5-Dihydro-thiazol-2-yl)-(4-methyl-indan-l-yl)-amine;
(4,5-Dihydro-thiazol-2-yl)-(3-methyl-indan-l-yl)-amine;
(4,5-Dihydro-oxazol-2-yl)-(3-methyl-indan-1-yl)-amine; and (4,5-Dihydro-thiazol-2-yl)-indan-l-yl-amine.
[48] One embodiment is a compound having a structure selected from:

N
N
HN~ ~ HN~ ~ HN~ ~ HNN~
H go ` H H

Br N N N~
HN~ HN HN~
H H H
I / \ I \ I
> > >
N N
HN
~ HNS~
GO-NH
/=N HN~

Cq HN~O~ /N
HN~S~
I \
and / .
[49] Another embodiment is a compound having the formula N
HN~N~
H
[50] Another embodiment is a compound having the formula N
HN--~~
~xY
[51] Another embodiment is a compound having the formula N
HN~N~
H
[52] Another embodiment is a compound having the formula N
HN--~N~

Pb H
Br [53] Another embodiment is a compound having the formula N
HN~N~
I \ H
/

[54] Another embodiment is a compound having the formula N
HN~N~
H
[55] Another embodiment is a compound having the formula N
HN~N~
H
\

[56] Another embodiment is a compound having the formula NH
N
HN, I

[57] Anoth~er/embodiment is a compound having the formula N
HN--S~
[58] Another embodiment is a compound having the formula HN--~S

[59] Another embodiment is a compound having the formula HN~O~

[60] Another embodiment is a compound having the formula N
HN--~S~
/

[61] Synthetic Methods [62] Reaction Scheme A, B, and C illustrate general methods for obtaining the amino-imidazolines, amino-oxazolines and amino-thiazolines.

Reaction Scheme A

0 NH2 C \>S-OH N~ ~
R3 NaCNBH3, R3 H 0 R3 H N

n n n cc ( R') 13 Npr=OHC' (R1)1-3 2-butanol (R')13 Formula 1 Formula 2 Formula 3 Reaction Scheme B

ci I ~

(R1~1 3// n (R1)1-3/~~~~ ?In Formula 4 Fo rm ula 5 Reaction Scheme C

H/N
NH2 N%~~

I ~

(R~~_3~~ Qn 2) H20, 'oo c (R')1-3I

Formula 6 Formula 7 Example A
Method A: Procedure for the preparation of (4,5-dihydro-lH-imidazol-2-yl)-(6-methyl-indan-1-yl)-amine, (083) G_~CI O NH2 \ OH a I\ NaCNBH3, b. AICI3 NH40Ac, i-PrOH

Intermediate 1 Intermediate 2 Intermediate 3 /N~
CN~S03H HN~NI
N
H \ H
2-Butanol /

A solution of 3-m-tolyl-propionic acid (Intermediate 1) (5.0 g, 29.5 mmol) in dichloromethane was treated with oxalyl chloride (4.5 g, 3.09 mL, 41.09 mmol) at rt and stirred for 2 h at rt. The mixture was concentrated and dissolved in dichloromethane and aluminum chloride (6.28 g, 37.62 mmol) was added in portions.
The mixture was quenched with ice. The residue was isolated in a typical aqueous workup to give 6-methyl-indan-l-one (Intermediate 2), (crude).
6-Methyl-indan-l-one, (Intermediate 2) (3.0 g, 20.0 mmol) in isopropanol (20 mL) was treated with sodiumcyanoborohydride(9.01 g, 143.5 mmol) and ammonium acetate (47.4 g, 615 mmol) and the reaction was refluxed for 16 hours.
The mixture was cooled to room temperature and basified with sodium hydroxide (10 mL). The residue was isolated in a typical aqueous workup to give, 6-methyl-indan-1-ylamine (Intermediate 3).

A mixture of 6-methyl-indan-1-ylamine (300 mg, 2.05 mmol) (Intermediate 3) and 4, 5-dihydro-lH-imidazole-2-sulfonic acid (339 mg, 2.2 mmol) in 2-butanol (10 mL) was refluxed for 16 h. The mixture was evaporated under reduced pressure.
This material was purified by chromatography on silica gel with 5% NH3-MeOH:
CH2C12 to (4,5-dihydro-lH-imidazol-2-yl)-(6-methyl-indan-1-yl)-amine (083) 152 mg (34%).
iHNMR (CD3OD, 300MHz): b= 7.32 (s, 1H), 7.24 (dd, J= 4.5, 13.2 Hz, 2H), 4.76-4.37 (m, 1H), 3.80 (s, 4H), 3.15-3.16 (m, 1H), 2.65-3.10 (m, 1H), 2.64-2.93 (m, 1H), 2.12-2.05 (m, 1H), 2.39 (s, 3H).

Example B
Method B: Procedure for the preparation of (4,5-dihydro-lH-imidazol-2-yl)-(5,7-dimethyl-1,2,3,4-tetrahydro-ngphthalen-1-yl)-amine (904) 0 NH2 CN~-S03H HNH
I~ NaCNBH31I~ H I
/ NH40 ,cA i-PrOH / 2-Butanol Intermediate 4 Intermediate 5 Intermediate 6 A solution of 5,7-dimethyl-3,4-dihydro-2H-naphthalen-l-one (commercially available, 12.3 g, 28.3 mmol) - (Intermediate 4) in isopropanol (100 mL) was treated with sodium cyanoborohydride (9.01 g, 143.5 mmol) and ammonium acetate (47.4 g, 615 mmol), and the reaction mixture was refluxed for 16 hours. The mixture was basified with sodium hydroxide (10 mL). The residue was isolated in a typical aqueous workup to give (6.5 g, 37.1 mmol) (Intermediate 5). A mixture of (500 mg, 5.7 mmol) (Intermediate 5) and 4, 5-dihydro-lH-imidazole-2-sulfonic acid (940 mg, 6.3 mmol) in 2-butanol (30 mL) was refluxed for 24 h. The mixture was evaporated under reduced pressure. This material was purified by chromatography on silica gel with 5% NH3-MeOH:CH2C12 to give (90 mg, 3.7 mmol,36%) of (4,5-dihydro-lH-imidazol-2-yl)-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (904).

Following a procedure similar to that for 904 afforded 631, 659, 629, 659, 323, 522, 380, 523, and 380.

Example C

Method C: Procedure for the preparation of:
O
O OH P\ N3 NHz NaBH4, MeOH (Ph0)2 ~ N3 I~ _ I c Ph3 DBU, Toluene THF:H20 (1;1) Intermediate 7 Intermediate 8 Intermediate 9 Intermediate 10 Sodium borohydride (1.3 g, 34.36 mmol, 1.0 eq) was added to a cooled (0 C) solution of 3-methyl-2,3-dihydro-lH-inden-l-one (Intermediate 7) (5.0 g, 34.2 mmol) in MeOH. The reaction mixture was stirred for 1 hour after which it was quenched with saturated NH4C1. The resulting mixture was extracted with Et20 (3x 50 mL), and the combined organic extracts was washed with H20 (3x 50 mL), brine (lx 50 mL), dried over MgS04 and concentrated to give 3-methyl-2,3-dihydro-lH-inden-l-ol (Intermediate 8) which was purified by column chromatography using hexane:EtOAc (4:1) as eluant.
Diphenylphosphoryl azide (10.40 mL, 48.26 mmol, 1.5 eq) was added to a cooled (0 C) solution of of 3-methyl-2,3-dihydro-lH-inden-l-ol (Intermediate 8) (4.77 g, 32.2 mmol) in toluene. The resulting mixture was stirred for a few minutes and 7.22 mL (1.5 eq) of DBU was added slowly. After stirring the reaction mixture overnight, it was diluted with toluene and washed with H20 (3x 50 mL), brine (lx 50 mL), dried over MgSO4 and concentrated to give 1-azido-3-methyl-2,3-dihydro-lH-indene (Intermediate 9) which was purified by column chromatography using hexane:EtOAc (4:1) as eluant.
To a solution of of 1-azido-3-methyl-2,3-dihydro-lH-indene (Intermediate 9) (5.53 g, 32.0 mmol) in THF:H20 (1:1) was added triphenyl phosphine (8.5 g, 1.01 eq) followed by KOH (1.8 g, 1.0 eq) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with H20 and slowly acidified with HC1 and the aqueous layer was washed with Et20 (3x 50 mL). The aqueous layer was then basified with NaOH (pH 14), extracted with Et20 (3x 50 mL), and the combined extracts was washed with H20 (lx 25 mL), brine (lx 25 mL), dried over K2C03 and concentrated to give 3-methyl-2,3-dihydro-lH-inden-l-amine (Intermediate 10), (4.47 g, 95% yield).

Example D

Method D: Procedure for the preparation of (R)- and (S)-4,5-dihydro-lH-imidazol-2-yl)-(4-methyl-indan-1-yl)1-amine (348 and 349) - optically pure enantiomers:

v Intermediate 11 H 1. R-(+)-2-methy1 CBS, 1. S-(-)-2-methyl CBS, H
~0 Ph (CH3)2S.BH3, THF 2. MeOHZS.BH3, THF Ph `N ILPh 2. MeOH
Me B Me' B
R-(+)-2-methyl CBS, OH OH S-(-)-2-methyl CBS, Me Me Intermediate 12 1.PPhO~P-N3 DBU, Ether 1. PPhhO,P-Ng DBU, Ether 2. PPh3, KOH, THF:H20 2. PPh3, KOH, THF:H20 H
HN-'N' HO-O~N NH2 NH2 HO O~N' HN~N' / H 0 N ~~ 0 N H
/
2-BuOH 2-BuOH
Me (+)-Rotation Me Me Me (-)-Rotation Intermediate 13 To a solution of 4-methyl indanone (5.0 g, 34.2 mmol) Intermediate 11 in anhydrous tetrahydrofuran (100 mL), the catalyst, R-(+)-2-methyl CBS. (5.1 mL, 5.1 mmol) was added. The reaction mixture was cooled to -18 C and BH3=SMe (4.78 mL, 23.94 mmol) was added slowly followed by the addition of methanol (40 mL). The reaction was warmed to rt and stirred for 14 hours. The mixture was evaporated under reduced pressure to afford (5.03 g) of Intermediate 12.

A solution of Intermediate 13 (2.0 g, 13.6 mmol) and diphenyl phoshoryl azide (3.52 mL, 16.32 mmol) in toluene (50 mL), was cooled to 0 C and DBU
(2.44m1, 16.32 mmol) was added. The reaction mixture was stirred for 7 hours.
The mixture was quenched with water. The residue was isolated in a typical aqueous workup to yield the intermediate azide. The azide (1.6g, 9.3 mmol) was dissolved in tetrahydrofuran (20 mL) and treated with triphenyl phosphine (2.46 g, 9.39 mmol) followed by the addition of potassium hydroxide (526 mg, 9.39 mmol) and water (5 mL). The reaction mixture was stirred at rt. overnight. The aqueous layer was basified with potassium hydroxide to pH 14, followed by an aqueous workup and concentrated under reduced pressure. The product was further purified with an acid/base workup to afford (1.35 g) of Intermediate 13.

A mixture of (Intermediate 13) (250 mgs, 1.7 mmol) and 4, 5-dihydro-lH-imidazole-2-sulfonic acid (292 mg, 1.87mmol) in 2-butanol (30 mL) was refluxed for 24 h. The mixture was evaporated under reduced pressure. This material was purified by chromatography on silica gel with 5% NH3-MeOH: CH2C12 to give 4, 5-dihydro-lH-imidazol-2-yl)-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-amine(348) respectively.

Example E
Method E: Procedure for the preparation of (4,5-Dihydro-oxazol-2-yl)-(3-methyl-indan-l-yl)-amine 603:

NHZ HN~ HN'~~
-~CI O
CI^~NCO Cq H H
CH reflux Intermediate 14 Intermediate 15 Intermediate 16 3-Methyl-indan-1-ylamine (Intermediate 14) (0.44 g, 3.0 mmol) in dichloromethane (10 mL) was added chloroethylisocyanate (0.32 mL, 3.3 mmol).
The solution was stirred at room temperature for 1.5 hour, and quenched with water.
The aqueous layer was extracted with dichloromethane (3 x 50). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. The filtrate was added silica gel, and the solvents were removed under vacuum. Purification by chromatography on silica gel (2 to 10% methanol in dichloromethane) gave a crude material, which was recrystalized in methanol/water to give Intermediate 15.
Intermediate 15 was refluxed in H20 (60 mL) for 1 hour. After cooling to room temperature, the reaction was basified with NaOH (pH 14), extracted in Ethyl acetate (3 x 50 mL). The pooled organic layers were washed with brine and dried over magnesium sulphate to give 603.

Example F
Method F: Procedure for the preparation of (4, 5-Dihydro-thiazol-2-yl)-(4-methyl-indan-l-yl)-amine 770:
N
/
NH2 CI~'NCS HNS
--Intermediate 17 Intermediate 18 1-(2,3-dichlorophenyl)-2-(pyridin-4-yl)ethanamine (Intermediate 17) (0.44 g, 3.0 mmol) in dichloromethane (10 mL) was added chloroethylisocyanate (0.32 mL, 3.3 mmol). The solution was stirred at room temperature for 1.5 hour, and quenched with water. The aqueous layer was extracted with dichloromethane (3x). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. The filtrate was added silica gel, and the solvents were removed under vacuum.
Purification by chromatography on silica gel (2 to 10% methanol in dichloromethane) gave a crude material, which was recrystalized in methanol/water to give (4,5-dihydro-thiazol-2-yl)-(4-methyl-indan-1-yl)-amine 770 as a solid (129 mg, 0.55 mmol, 81% yield).

The following compounds have been synthesized by one of the methods described above:

(4, 5-Dihydro-lH-imidazol-2-yl)-(4-methyl-indan-1-yl)-amine, 629:
Method B:

iHNMR (CD3OD, 500MHz): b= 7.08-7.15 (m, 3H), 4.99 (t, J= 7.5 Hz, 1H), 3.68 (s, 4H), 2.97-3.02 (m, 1H), 2.77-2.81 (m, 1H), 2.55-2.62 (m, 1H).

[(1R)-(4, 5-Dihydro-lH-imidazol-2-yl)-(4-methyl-indan-1-yl)]-amine, 348:
Method D:
iHNMR (CD3OD, 500MHz): b= 7.08-7.15 (m, 3H), 4.99 (t, J= 7.5 Hz, 1H), 3.68 (s, 4H), 2.97-3.02 (m, 1H), 2.77-2.81 (m, 1H), 2.55-2.62 (m, 1H).

[(1S)-(4, 5-Dihydro-lH-imidazol-2-yl)-(4-methyl-indan-1-yl)]-amine, 349:
Method D:
iHNMR (CD3OD, 500MHz): b= 7.08-7.15 (m, 3H), 4.99 (t, J= 7.5 Hz, 1H), 3.68 (s, 4H), 2.97-3.02 (m, 1H), 2.77-2.81 (m, 1H), 2.55-2.62 (m, 1H).
(4-Bromo-indan-1-yl)- (4, 5-dihydro-lH-imidazol-2-yl)-amine, 631:
Method B:

iHNMR (DMSO, 300MHz): b= 7.6 (d, J= 6 Hz, 1H), 7.20-7.40 (m, 2H), 5.05-5.20 (m, 1H), 3.65 (s, 4H), 2.70-3.05 (m, 2H), 2.50-2.60 (m, 1H), 1.6-2.0 (m, 1H).

(4, 5-Dihydro-lH-imidazol-2-yl)-indan-1-yl-amine, 523:
Method B:
iHNMR (DMSO, 300MHz): b 7.31 - 7.25 (m, 4 H), 5.02 (t, J= 7.08 Hz, 1 H), 3.66 (m, 4H), 2.95 - 2.98 (m, 1 H), 2.81 - 2.85 (m, 1 H), 2.48-2.53 (m, 1 H), 1.84-1.91 (m, 1 H).

[(1S (4, 5-Dihydro-lH-imidazol-2-yl)-indan-1-yl] amine, 380:
Method B:

iHNMR (CD3OD, 500MHz): b= 7.22-7.40 (m, 4 H), 5.02 (t, J= 7.08 Hz, 1 H), 3.74 (s, 4H), 2.83-3.16, (m, 1 H), 2.53-2.71 (m, 2 H), 1.95-1.99 (m, 1 H).

(4, 5-Dihydro-lH-imidazol-2-yl)-(6-methyl-indan-1-yl)-amine, 083:
Method A:

iHNMR (CD3OD, 300MHz): b= 7.32 (s, 1H), 7.24 (dd, J= 4.5, 13.2 Hz, 2H), 4.76-4.37 (m, 1H), 3.80 (s, 4H), 3.15-3.16 (m, 1H), 2.65-3.10 (m, 1H), 2.64-2.93 (m, 1H), 2.12-2.05 (m, 1H), 2.39 (s, 3H).

(4, 5-Dihydro-lH-imidazol-2-yl)-indan-2-yl-amine, 522:
Method B:

iHNMR (DMSO, 300MHz): b= 7.26-7.28 (m, 4H), 4.24-4.30 (m, 1H), 3.62 (s, 4H), 3.34 (dd, J= 6 Hz, 15 Hz, 2H,), 3.20 (dd, J= 9 Hz, 18 Hz, 2H).
(4,5-Dihydro-lH-imidazol-2-yl)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine, 639:
Method B:

iHNMR (CD3OD, 300MHz): b= 7.26-7.14 (m, 4H), 4.65 (t, J= 6.0 Hz, 1H), 3.74 (s, 4H), 2.65-2.90 (m, 2H), 1.86-2.08 (m, 3H), 1.42-1.47 (m, 1H).

[(1S (4,5-Dihydro-lH-imidazol-2-yl)-(1,2,3,4-tetrahydro-naphthalen-1-yl)]
amine, 323 :
Method B:

iHNMR (CD3OD, 500MHz): b= 7.06 - 7.37 (m, 4H), 4.65 (t, J= 5.0 Hz, 1H), 3.74 (s, 4H), 2.72-2.98 (m, 2H), 1.77-2.23 (m, 3H), 1.44-1.48 (m, 1H).

(4, 5-Dihydro-lH-imidazol-2-yl)-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-l-yl)-amine, 904:
Method B:
'HNMR (CD3OD, 500MHz): b= 6.94 (d, 2H), 4.61-4.67 (m, 1H), 3.90 (s, 4H), 2.63-2.60 (m, 2H), 1.82-1.98 (m, 4H), 2.28 (s, 3H), 2.28 (s, 3H).

(4, 5-Dihydro-oxazol-2-yl)-(4-methyl-indan-1-yl)-amine, 770:
Method E:
'HNMR (CD3OD, 300MHz): b= 7.13-7.19 (m, 3H), 5.20 (t, J= 10 Hz, 1H), 4.06-4.93 (m, 2H), 3.60-3.63 (m, 2H), 3.00-3.06 (m, 1H), 2.83-2.88 (m, 1H), 2.60-2.67 (m, 1H), 2.30 (s, 3H), 1.99-2.05 (m, 1H) .

(4, 5-Dihydro-thiazol-2-yl)-(4-methyl-indan-1-yl)-amine, 075:
Method F:
iHNMR (CDC13, 500MHz): b= 6.97-7.19 (m, 3H), 5.50 (t, J= 10 Hz, 1H), 3.30-3.41 (m, 2H), 3.19-3.22 (m, 1H), 3.02-3.07 (m, 1H), 2.68-2.74 (m, 1H), 2.81-2.84 (m, 1H), 2.19 (s, 3H), 1.85-1.88 (m, 1H) .

(4, 5-Dihydro-thiazol-2-yl)- (3-methyl-indan-1-yl)-amine, 604:
Method F:
iHNMR (DMSO, 500MHz): b= 7.38 (d, J= 10 Hz, 1H), 7.12-7.26 (m, 3H), 5.28 (t, J
= 10 Hz, 1H), 3.90-3.93 (m, 2H), 3.28-3.36 (m, 3H), 2.14-2.16 (m, 1H), 1.97-2.13 (m, 1H), 1.25 (d, 3H, J= 10 Hz).

(4, 5-Dihydro-oxazol-2-yl)-(3-methyl-indan-1-yl)-amine , 603:
Method E:
'HNMR (DMSO, 500MHz): b= 7.34 (d, J= 10 Hz, 1H), 7.16-7.21 (m, 3H), 5.04(t, J
= 10 Hz, 1H), 4.16 (t, J= 5 Hz, 1H), 3.59-3.63 (m, 3H), 3.29 (m, 1H), 2.08-2.10 (m, 1H), 1.94-1.90 (m, 1H), 1.17 (d, 3H, J= 5 Hz) .
(4, 5-Dihydro-thiazol-2-yl)-indan-1-yl-amine, 524:
Method F:
'HNMR (CDC13, 300MHz): b= 6.89-7.34 (m, 4H), 5.21 (s, J= 4.5 Hz, 1H), 4.01-4.07 (m, 2H), 3.34-3.39 (m, 2H), 2.82-2.96 (m, 2H), 2.59-2.67 (m, 1H), 1.91-1.99 (m, 1H).
(4, 5-Dihydro-oxazol-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine, 747:
Method E:
'HNMR (CDC13, 300MHz): b= 8.42 (d, J= 6 Hz, 1H), 7.42 (d, J= 6 Hz, 1H), 7.13 (dd, J= 6, 9 Hz, 1H), 4.88-4.69 (m, 3H), 3.99-3.85 (m, 2H), 2.95-2.87 (m, 1H), 2.80-2.71 (m, 1H), 2.30-2.23 (m, 1H), 2.08-2.01 (m, 2H), 1.89-1.77 (m, 1H).
(4, 5-Dihydro-oxazol-2-yl)-(5,6,7,8-tetrahydro-quinoxalin-5-yl)-amine, 772:
Method E:

iHNMR (CD3OD, 500MHz): b= 8.43 (dd, J= 5, 15 Hz, 2H), 4.79 (t, J= 5 Hz, 1H), 4.39-4.32 (m, 2H), 3.77 (t, J= 10 Hz, 2H), 3.06-2.93 (m, 3H), 2.21-2.19 (m, 1H), 2.01-1.96 (m, 2H).
[63] Biological Data [64] Receptor Selection and Amplification Technology (RSAT) assay [65] The RSAT assay measures a receptor-mediated loss of contact inhibition that results in selective proliferation of receptor-containing cells in a mixed population of confluent cells. The increase in cell number is assessed with an appropriate transfected marker gene such as 0-galactosidase, the activity of which can be easily measured in a 96-well format. Receptors that activate the G protein, Gq, elicit this response. Alpha2 receptors, which normally couple to Gi, activate the RSAT
response when coexpressed with a hybrid Gq protein that has a Gi receptor recognition domain, called Gq/i5.
[66] NIH-3T3 cells are plated at a density of 2x106 cells in 15 cm dishes and maintained in Dulbecco's modified Eagle's medium supplemented with 10% calf serum. One day later, cells are cotransfected by calcium phosphate precipitation with mammalian expression plasmids encoding p-SV-0-galactosidase (5-10 g), receptor (1-2 g) and G protein (1-2 g). 40 g salmon sperm DNA may also be included in the transfection mixture. Fresh media is added on the following day and 1-2 days later, cells are harvested and frozen in 50 assay aliquots. Cells are thawed and 100 l added to 100 l aliquots of various concentrations of drugs in triplicate in 96-well dishes. Incubations continue 72-96 hr at 37 C. After washing with phosphate-buffered saline, 0-galactosidase enzyme activity is determined by adding 200 l of the chromogenic substrate (consisting of 3.5 mM o-nitrophenyl-(3-D-galactopyranoside and 0.5% nonidet P-40 in phosphate buffered saline), incubating overnight at and measuring optical density at 420 nm. The absorbance is a measure of enzyme activity, which depends on cell number and reflects a receptor-mediated cell proliferation. The efficacy or intrinsic activity is calculated as a ratio of the maximal effect of the drug to the maximal effect of a standard full agonist for each receptor subtype. Brimonidine, also called UK14304, the chemical structure of which is shown below, is used as the standard agonist for the alpha2A, alpha2B and alphazC

receptors. The EC50 is the concentration at which the drug effect is half of its maximal effect.
Br H
.N ~ NYN>
N I / HN-/

[67] Brimonidine [68] The results of the RSAT assay with several exemplary compounds of the invention are disclosed in Table 1 above together with the chemical formulas of these exemplary compounds. EC50 values are nanomolar. ND stands for "not determinable" at concentrations less than 10 micromolar. IA stands for "intrinsic activity."

Table 1 Structure Alpha 2B Alpha 2C Alpha 2A
N
HN~N~
/ I H
\
5.7 429 nd 629 (98) (38) (20) N
HN~N~
H
33.4 nd nd (106) (11) (11) N
HN-~N~
/ H 4.5 82 nd ~ ~ (125) (62) (16) N
HN~N~
Pb H 12.2 nd nd (71) (12) (7) Br N
HN--N~
w H 17 207 nd (93) (46) (3) N
HN~N~
H
43 nd nd (82) (11) (4) Structure Alpha 2B Alpha 2C Alpha 2A
N
HN~N~
H
473 nd nd 083 (34) (7) (7) NH
HN N 61 nd nd (36) (5) (5) N
HN ~S~

3.4 23 143 (138) (96) (57) HN~S~

(99) (41) (25) HN--~O

2.2 19.8 7 (112) (50) (25) N
HN ~S~

w 7.5 54 nd 524 (107) (102) (14) [69] Methods of formulating these compounds are well known in the art. For example, United States Patent No. 7,141,597 (especially column 10, line 27 to column 14, line 47) contains information that may be used for general guidance.
Similar relevant information is also available in numerous other sources. The biological activity of the compounds disclosed herein (e.g. Table 1) may be used for additional general guidance on dosage, depending on the particular use of a compound.
[70] The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. However, it is apparent for one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same result. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention is to be governed only by the lawful construction of the claims.

Claims (20)

1. A method of treating pain comprising administering a compound to a mammal in need thereof, said compound having a structure wherein X is O, S, or NH;
n is 2 or 3;
R a, R b, R c, and R d are stable moieties independently consisting of: from 0 to 4 carbon atoms, from 0 to 10 hydrogen atoms, from 0 to 2 oxygen atoms, from 0 to 1 sulfur atoms, from 0 to 1 nitrogen atoms, from 0 to 3 fluorine atoms, from 0 to 1 chlorine atoms, and from 0 to 1 bromine atoms; and Re is H or C1-4 alkyl.
2. The method of claim 1 wherein X is O.
3. The method of claim 1 wherein X is S.
4. The method of claim 1 wherein X is NH.
5. The method of claim 1 wherein R a, R b, R c, and R d are independently selected from H, methyl, ethyl, C3 alkyl, and C4 alkyl, F, Cl, Br, -CH2OH, -CH2NH2, -CHNH(C1-4 alkyl), -CN(C1-4 alkyl)2, -CH2CN, and CF3.
6. The method of claim 1 wherein R a, R b, R c, and R d are independently selected from H, methyl, ethyl, F, Cl, Br, -CH2CN, and CF3.
7. The method of claim 5 wherein Re is H.
8. The method of claim 5 wherein Re is methyl.
9. The method of claim 2, said compound having a structure
10. The method of claim 1 wherein the pain is allodynia.
11. A method of reducing intraocular pressure comprising administering a compound to a mammal in need thereof, said compound having a structure wherein X is O, S, or NH;
n is 2 or 3;
R a, R b, R c, and R d are stable moieties independently consisting of: from 0 to 4 carbon atoms, from 0 to 10 hydrogen atoms, from 0 to 2 oxygen atoms, from 0 to 1 sulfur atoms, from 0 to 1 nitrogen atoms, from 0 to 3 fluorine atoms, from 0 to 1 chlorine atoms, and from 0 to 1 bromine atoms; and R e is H or C1-4 alkyl.
12. The method of claim 1 wherein X is O.
13. The method of claim 1 wherein X is S.
14. The method of claim 1 wherein X is NH.
15. The method of claim 1 wherein R a, R b, R c, and R d are independently selected from H, methyl, ethyl, C3 alkyl, and C4 alkyl, F, Cl, Br, -CH2OH, -CH2NH2, -CHNH(C1-4 alkyl), -CN(C1-4 alkyl)2, -CH2CN, and CF3.
16. The method of claim 1 wherein Ra, Rb, R , and Rd are independently selected from H, methyl, ethyl, F, Cl, Br, -CH2CN, and CF3.
17. The method of claim 5 wherein Re is H.
18. The method of claim 5 wherein Re is methyl.
19. The method of claim 2, said compound having a structure
20. A compound having a structure selected from:

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